This invention relates to a multiple-release formulation and a process for producing it. The invention relates particularly to a formulation that has a drug core surrounded by a release control layer to present a mechanism by which the drug in the core is rapidly released after a predetermined delay in time. The invention further; relates to a formulation which also has a rapid drug release portion provided outside the release control layer so that the drug can be released more than once at intervals after single dosing. Further in addition, the invention relates to a formulation that incorporates a plurality of drugs in both a core and one or more drug release layers so that different active ingredients can be released at different times.
Oral controlled-release formulations have the advantage of reducing the frequency of dosing so that the burden on patients is reduced to improve their compliance. As examples of the technology for oral controlled-release formulations, sol-called sustained-release formulations which release the drug in a sustained manner to main therapeutic blood levels are widely known (e.g. sustained-release theophylline formulation xe2x80x9cTheo-Durxe2x80x9d and slow-release propranolol hydrochloride formulation). A problem with such sustained-release formulations that maintain the drug blood level within the therapeutic range before excretion is that some drugs have a high likelihood for developing tolerance. As a further problem, drugs that are sensitive to first-pass metabolism in the liver have lower bioavailability when administered in the sustained-release dosage form than when they are administered in immediate-release dosage forms. These kinds of drugs are effectively administered in formulations that provide more than one release by single dosing. It is sometimes desired that two drugs be allowed to act by administering them at different times as in a case where the therapeutic effect of one drug can be improved by a preliminary or post-treatment with the other drug; in these situations, it is effective to use controlled-release formulations that allow for more than one release of different drugs at different times after single dosing.
As far as the present inventors know, the conventional pharmaceutical formulation techniques that allow for more than one drug release with a view to reducing the frequency of dosing include the use of matrix-forming water-soluble polymers or waxes as a release control base that surround the drug core containing a water-swellable disintegrant (see, for example, Japanese Patent Public Disclosure Nos. 246512/1987 and 273816/1992). However, the water-soluble polymer base is difficult to use with drugs that are labile in the presence of water in the polymer base. The matrices made of waxes are so labile under elevated temperatures that the drug release characteristics may potentially change during storage. What is more, waxes cannot generally be applied to drugs that are either reactive or miscible with them. Thus, no multiple-release formulations have been developed that can be applied to control the release of a broader range of drugs and which do not experience any change in drug release characteristics during storage.
In view of these problems of the prior art, the present invention aims at providing a formulation that uses a release controlling non-wax base of which the water content can be easily controlled and which permits more than one drug release, that is capable of precise control over the time interval (or xe2x80x9ctime lagxe2x80x9d) between individual releases, and that is less sensitive to the environment in the gastrointestinal tract. The invention also aims at providing a technology for producing the formulation.
The present inventors made intensive studies in order to solve the above-mentioned problems of the prior art. As a result, they found that when at least one low-molecular weight substance having low dissolution rate under physiological conditions as selected from among fumaric acid, DL-tryptophan and L-tyrosine was incorporated as a base for a release control layer in a formulation, it was not only easy to control the water content of the base but controlled drug release with desired time lag could also be achieved without using waxes as the release control base. The present invention has been accomplished on the basis of this finding.
Hence, the present invention provides a controlled-release formulation that comprises essentially a core containing at least one drug the release of which is to be controlled, a release control layer that is produced by adding pharmaceutically acceptable additives to at least one base selected from among fumaric acid, DL-tryptophan and L-tyrosine and which is a coating layer substantially free of drugs the release of which is to be controlled, and a drug release layer that contains at least one drug the release of which is to be controlled, said formulation satisfying the following conditions:
(1) the core be located in the innermost portion of the controlled-release formulation;
(2) said formulation have at least one release control layer covering the core, with at least one additional release control layer and/or drug release layer being optionaly present;
(3) the release control layer(s) alternate with the drug release layer(s);
(4) the outermost layer may be either the release control layer or the drug release layer;
(5) if the outermost layer is the drug release layer, it may cover all or part of the surface of the underlying release control layer;
(6) the drugs to be contained in the core and the drug release layer of said formulation should be selected independently of each other;
(7) the core and the drug release layers may be formulated to permit immediate release or slow release of the drugs contained; and
(8) if two or more drugs are to be contained in the core and the drug release layer(s) of said formulation, said core and a single drug release layer may each be composed of more than one layer containing only one drug.
Thus, according to the present invention, there is provided a controlled-release formulation having such a portion that a core formulated to permit rapid or slow release of one or more drugs is covered with a release control layer that is prepared by adding pharmaceutically acceptable additives to at least one base selected from among fumaric acid, DL-tryptophan and L-tyrosine and which is substantially free from the drugs the release of which is to be controlled.
The present invention also provides a process for producing a controlled-release formulation that comprises at least the following step A:
A. molding a core containing at least one drug the release of which is to be controlled and forming a release control layer by covering said core with a component that has a pharmaceutically acceptable additive incorporated in at least one base selected from among fumaric acid, DL-tryptophan and L-tyrosine and which is substantially free of the drugs thee release of which is to be controlled and thereby forming a shape of a dual structure;
said step A being optionally followed by the following step B, or the following steps B and C, or the following steps B-D, or the following steps B-E:
B. covering or overlaying the shape of a dual structure with a component containing at least one drug the release of which is to be controlled and thereby forming a drug release layer;
C. covering the shape obtained in said step B with a component that has a pharmaceutically acceptable additive incorporated in at least one base selected from among fumaric acid, DL-tryptophan and L-tyrosine and which is substantially free from the drugs the release of which is to be controlled and thereby forming a release control layer;
D. covering or overlaying the shape obtained in said step C with a component containing at least one drug the release of which is to be controlled and thereby forming a drug release layer; and
E. repeating said step C of forming a release control layer and said step D of forming a drug release layer at least once to produce the desired controlled-release formulation which satisfies the above-mentioned conditions (1)-(8).